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ICOSR 2011—Gene Expression Studies Highlight Candidate Schizophrenia Genes

As part of our ongoing coverage of the 2011 International Congress on Schizophrenia Research (ICOSR), held 2-6 April in Colorado Springs, Colorado, we bring you session summaries from some of the attendees. For this report, we thank Allison A. Curley of the University of Pittsburgh, Pennsylvania.


3 May 2011. A number of risk genes have been identified in schizophrenia, and substantial research is now focused on the molecular mechanisms through which these genes may confer risk. Given that the majority of identified genetic variants are noncoding single nucleotide polymorphisms (SNPs), it is hypothesized that these SNPs are changing gene expression, perhaps by altering transcriptional activity or alternative splicing (Kleinman et al., 2011). The four speakers of a 6 April morning symposium discussed a wide variety of genes implicated in schizophrenia, and highlighted their recent work measuring changes in gene expression using case-control and developmental cohorts.

First up was Joel Kleinman from the National Institute of Mental Health in Bethesda, Maryland, who discussed a wide variety of research using postmortem human tissue to inform how risk alleles and haplotypes are related to schizophrenia. Recently, the study of intermediate phenotypes in schizophrenia has received much attention. Kleinman pointed out that a major advantage of studying postmortem human tissue is that it provides access to mRNA, “the ultimate intermediate phenotype, in terms of proximity to the gene” (Kleinman et al., 2011). Delving into recent studies conducted at the NIMH, he first discussed normal developmental and abnormal schizophrenia expression patterns of the alternative transcripts of two schizophrenia candidate genes: the potassium channel KHCN2 and neuregulin 1 (NRG1). Allelic variation in both of these schizophrenia risk genes is associated with mRNA expression of alternative transcripts that are expressed at high levels in the fetal brain.

Next, Kleinman discussed a genomewide association study of allelic variation with transcription and noted that his group has found over 10,000 variations associated with expression. These exciting data are forthcoming, and Kleinman announced plans to make this dataset public in the next few months. He also discussed his recent preliminary epigenetic studies from healthy subjects, examining changes in microRNAs and methylation across development. He reported that genes that are expressed at higher levels in fetal brain but at lower levels postnatally have a disproportionate number of miRNA binding sites. He concluded with data demonstrating the age-dependence of genomewide methylation, with the largest change in methylation occurring during the fetal period.

The next speaker was Amanda Law, also from NIMH, who focused on a specific risk gene implicated in schizophrenia, neuregulin 3 (NRG3). She showed that genetic variation in intron 1 of NRG3, a specific ligand for the receptor ErbB4, is associated with schizophrenia and with positive symptom severity in patients (Kao et al., 2010). She also demonstrated that NRG3 undergoes very complex splicing, having identified at least 20 alternative splice variants that are expressed during development as well as in the adult brain. This suggests an important role for NRG3 in both the development and maintenance of the brain. Law also demonstrated that a common risk variant for NRG3 is associated with NRG3 isoform mRNA expression in both fetal and adult brain, and is increased in the prefrontal cortex in schizophrenia. Finally, moving downstream, she discussed more recent studies demonstrating that NRG3 activates the AKT1 signaling pathway.

The third speaker of the symposium, again from NIMH, was Barbara Lipska. In a departure from the two preceding talks, Lipska discussed three genes that have been strongly implicated in schizophrenia through their function, despite exhibiting only a weak genetic risk for schizophrenia. She examined DLG4, the gene that encodes the scaffolding protein PSD95, as well as two dopamine receptor genes, DRD1 and DRD2. Using a large cohort, she examined dorsolateral prefrontal cortex (DLPFC) and hippocampal tissue from control, schizophrenia, major depression, and bipolar disorder subjects. Lipska reported that the fetal period appears to be a critical time for the switching on or off of splice variants of these genes, and reported altered expression of the splice variants in schizophrenia. Subjects with major depression and bipolar disorder also exhibited altered expression patterns that were distinct from those in schizophrenia. Additionally, she demonstrated that variants of these genes predict the expression levels of their transcripts.

The final speaker of the symposium was Alessandro Bertolino from the University of Bari in Italy. Unlike the three previous postmortem tissue-oriented talks, Bertolino described studies of the dopamine DRD2 receptor in the brains of living schizophrenia subjects, reminding us again of the importance of intermediate phenotypes in uncovering how genetic variation modifies brain function. After noting that an intermediate phenotype must, by definition, also be present in the healthy siblings of patients (Callicott et al., 2003), he described one phenotype that has been extensively examined by his group: working memory deficits in the DLPFC of schizophrenia subjects and unaffected siblings (Callicott et al., 2000; Callicott et al., 2003). He reviewed evidence suggesting that DRD2 plays an important role in working memory processing and performance (Wang et al., 2004). As we heard from Lipska earlier in the symposium, the DRD2 gene is alternatively spliced into short and long variants. Bertolino demonstrated that an alteration in the balance of these variants is associated with working memory and attentional control deficits (Zhang et al., 2007), mediated at least in part by striatal dopamine (Bertolino et al., 2010). He also reported that interactions between genetic variations of DRD2 and AKT1 partially explain the variance in attentional control and response to treatment with olanzapine (Blasi et al., 2011). Finally, he discussed recent data examining changes further downstream in the dopamine signaling pathway. Genetic variation in GSK-3β is associated with prefrontal activity and behavioral performance during working memory and attentional tasks, and correlates with expression in other pathway genes.

In summary, this symposium discussed recent work aimed at uncovering the molecular mechanisms underlying several schizophrenia risk genes that encompass a wide variety of neurotransmitter systems and signaling pathways. As detailed specifically by Kleinman, but evidenced by data shown in each of the first three talks, postmortem brain tissue is a valuable tool for investigating the molecular mechanisms through which schizophrenia risk genes exert their actions (Kleinman et al., 2011). Importantly, this method can be used effectively in control tissue, which eliminates potential confounds of schizophrenia brains such as medication and illness chronicity (Kleinman et al., 2011). Furthermore, this allows for the assessment of developmental changes in gene expression. Indeed, the data presented here demonstrate that schizophrenia risk alleles are, in fact, associated with altered gene expression and function. Moving away from postmortem research, Bertolino’s talk also highlighted the importance of using intermediate phenotypes to assess gene function in schizophrenia, focusing specifically on the DRD2 signaling pathway and its effect on working memory and attention. It is an exciting time in schizophrenia genetic research, as the mechanisms underlying genetic variants in the illness are beginning to come to light. Harnessing the power of this wealth of genetic data already has informed specific hypotheses and eventually treatment strategies in the illness, and undoubtedly will continue to do so.—Allison A. Curley.

Comments on Related News


Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms

Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.

References:

Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover